We present in this study an optimization of a preliminary pharmacophore model for 5-HT(7)R antagonism, with the incorporation of recently reported ligands and using an efficient procedure with the CATALYST program. The model consists of five features: a positive ionizable atom (PI), a H-bonding acceptor group (HBA), and three hydrophobic regions (HYD). This model has been supported by the design, synthesis, and biological evaluation of new naphtholactam and naphthosultam derivatives of general structure I (39-72). A systematic structure-affinity relationship (SAFIR) study on these analogues has allowed us to confirm that the model incorporates the essential structural features for 5-HT(7)R antagonism. In addition, computational simulation of the complex between compound 56 and a rhodopsin-based 3D model of the 5-HT(7)R transmembrane domain has permitted us to define the molecular details of the ligand-receptor interaction and gives additional support to the proposed pharmacophore model for 5-HT(7)R antagonism: (i) the HBA feature of the pharmacophore model binds Ser(5.42) and Thr(5.43), (ii) the HYD1 feature interacts with Phe(6.52), (iii) the PI feature forms an ionic interaction with Asp(3.32), and (iv) the HYD3 (AR) feature interacts with a set of aromatic residues (Phe(3.28), Tyr(7.43)). These results provide the tools for the design and synthesis of new ligands with predetermined affinities and pharmacological properties.

Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2-cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.

Funding SourcesGlaxoSmithKline acknowledges financial support from Medicines for Malaria Venture (MMV). ' ACKNOWLEDGMENTGlaxoSmithKline acknowledges the perceptive and helpful advice from Jeremy Burrows and Mike Witty.

We report the synthesis of a new set of compounds of general structure I (1-20) with structural modifications in the pharmacophoric elements of the previously reported lead UCM-5600. The new derivatives have been evaluated for binding affinity at 5-HT(7) and 5-HT(1A) receptors. The influence of the different structural features in terms of 5-HT(7)/5-HT(1A) receptor affinity and selectivity was analyzed by computational simulations of the complexes between compounds I and beta(2)-based 3-D models of these receptors. Compound 18 (HYD(1) = 1,3-dihydro-2H-indol-2-one; spacer = -(CH(2))(4)-; HYD(2) + HYD(3) = 3,4-dihydroisoquinolin-2(1H)-yl) exhibits high 5-HT(7)R affinity (K(i) = 7 nM) and selectivity over the 5-HT(1A)R (31-fold), and has been characterized as a partial agonist of the human 5-HT(7)R.